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16 Volume 3, Number 3 • May 2014 • www.gahmj.com

GLOBAL ADVANCES IN HEALTH AND MEDICINE

Original Research

INTRODUCTION Small intestinal bacterial overgrowth (SIBO) is

defined as an increase in the concentration of bacteria of more than 100 000 colony-forming units per mL of proximal jejunal fluid.1 Although the overall preva-lence of SIBO in the general public is unknown, a meta-analysis has shown that the prevalence of SIBO is approximately 56% among patients with irritable bowel syndrome (IBS).2 At present, the prevalence of SIBO in the community or in a tertiary-care gastroenter-ology referral practice remains unknown. SIBO is becoming an increasingly significant problem in clini-cal practice as its manifestations can be protean and range from a full-blown enteropathy causing profound malabsorption and malnutrition simulating celiac dis-ease to mild symptoms that overlap with IBS.1 There are several factors involved in the pathogenesis of SIBO that have in common a disruption in the natural protective antibacterial mechanisms of the gut as shown in Tables 1-3.3 These factors, alone or in combination, can predis-pose the gut toward dysbiosis and favor the growth and colonization of aerobes and anaerobes in the proximal jejunum and may provide barrier(s) from achieving durable remission of symptoms following treatment.10

ORIGINAL RESEARCH

Herbal Therapy Is Equivalent to Rifaximin for the Treatment of Small Intestinal Bacterial Overgrowth VictorChedid,MD,United States;SameerDhalla,MD,United States;JohnO.Clarke,MD,United States;

BaniChanderRoland,MD,United States;KerryB.Dunbar,MD,United States;JoyceKoh,MD,United States;

EdmundoJustino,MD,United States;EricTomakin,RN,United States;GerardE.Mullin,MD,United States

Author Affiliations

UniversityofPittsburgh

MedicalCenter,

DepartmentofInternal

Medicine,Pittsburgh,

Pennsylvania

(DrChedid);TheJohns

HopkinsHospital,


Medicine,Divisionof

Gastroenterology,

Baltimore,Maryland

(DrsDhalla,Clarke,

Roland,Koh,andMullin

andMrTomakin);

UniversityofTexas

Southwestern,


Medicine,Divisionof

Gastroenterology,Dallas,

Texas(DrDunbar);

TrinityHealthCenter-


Medicine-Divisionof

Gastroenterology,Minot,

NorthDakota

(DrJustino).

Correspondence

GerardE.MullinMD

[email protected]

Citation

GlobalAdvHealthMed.

2014;3(3):16-24.

DOI:10.7453/

gahmj.2014.019

Key Words

Irritablebowel

syndrome(IBS),

rifaximin,Antibiotics,

SmallIntestine

BacterialOvergrowth

(SIBO),Dysbiosis,

Complementaryand

AlternativeMedicine

(CAM),HerbalTherapies.

Disclosures

Theauthorscompleted

theICMJEFormfor

DisclosureofPotential

ConflictsofInterest,and

nonewasreported.

ABSTRACTObjective: Patients with small intestine bacterial overgrowth (SIBO) have chronic intestinal and extraintestinal symptomatology which adversely affects their quality of life. Present treatment of SIBO is limited to oral antibiotics with variable success. A growing number of patients are interested in using complementary and alternative therapies for their gastrointestinal health. The objective was to determine the remission rate of SIBO using either the antibi-otic rifaximin or herbals in a tertiary care referral gastroenterology practice. Design: One hundred and four patients who tested positive for newly diagnosed SIBO by lactulose breath testing (LBT) were offered either rifaximin 1200 mg daily vs herbal therapy for 4 weeks with repeat LBT post-treatment.Results: Three hundred ninety-six patients underwent LBT for suspected SIBO, of which 251 (63.4%) were positive 165 underwent treatment and 104 had a follow-up LBT. Of the 37 patients who received herbal therapy, 17 (46%) had a negative follow-up LBT compared to 23/67 (34%) of rifaximin users (P=.24). The odds ratio of having a negative LBT after taking herbal therapy as compared to rifaximin was 1.85 (CI=0.77-4.41, P=.17) once adjusted for age, gender, SIBO risk factors and IBS status. Fourteen of the 44 (31.8%) rifaximin non-responders were offered herbal rescue therapy, with 8 of the 14 (57.1%) having a negative LBT after completing the rescue herbal therapy ,while 10 non-responders were offered triple antibiotics with 6 responding (60%, P=.89). Adverse effects were reported among the rifaximin treated arm including 1 case of anaphylaxis, 2 cases of hives, 2 cases of diarrhea and 1 case of Clostridium difficile. Only one case of diarrhea was reported in the herbal therapy arm, which did not reach statistical significance (P=.22). Conclusion: SIBO is widely prevalent in a tertiary referral gastroenterology practice. Herbal therapies are at least as effective as rifaximin for resolution of SIBO by LBT. Herbals also appear to be as effective as triple antibiotic therapy for SIBO rescue therapy for rifaximin non-responders. Further, prospective studies are needed to validate these find-ings and explore additional alternative therapies in patients with refractory SIBO.

What is the current knowledge?

Smallintestinalbacterialovergrowth(SIBO)iswidelypreva-lentamongpatientswiththeirritablebowelsyndrome(IBS)andisassociatedwithaworseningofsymptomsandqualityoflife.

CurrenttreatmentofSIBOispresentlylimitedtoantibioticswithavariableresponserateandnonehavebeenapprovedbytheUSFederalDrugAdministration(FDA).

SIBOisoftentreatedwithacourseofrifaximin1200mg/dayfor10-14days,whichisexpensiveandnotroutinelycov-eredbymanycommercialhealthplansintheUnitedStates.

ThemajorityofIBSpatientsusecomplementaryandalter-nativetherapiestocontrolsymptomsandareoftenlookingformore“natural”optionstotreattheirdisease.

What is new here?

ThehighprevalencerateforSIBOof64%inatertiarycarereferralgastroenterologypractice.

TheresponseratefornormalizingbreathhydrogentestinginpatientswithSIBOwas46%forherbaltherapiesvs34%forRifaximin.

HerbaltherapymaybeaneffectivetreatmentforpatientswithSIBO.

PatientswithSIBOrefractorytorifaximincanbegiventhechoiceofherbaltherapyasrescuetherapy.

Tayma S. Shaya

www.gahmj.com • May 2014 • Volume 3, Number 3 17Original Research

HERBAL THERAPY FOR THE TREATMENT OF SMALL INTESTINAL BACTERIAL OVERGROWTH

Currently, lactulose breath testing (LBT) is the most commonly used procedure for diagnosing SIBO.11,12 LBT is useful as an indirect testing method for SIBO, given that the human gastrointestinal (GI) tract does not absorb or use lactulose, which is metabolized by bacteria to produce hydrogen and methane gas. These gases are then measured by gas chromatography.13 Once suspected SIBO is diagnosed, it should be treated to prevent its myriad of adverse consequences.14-17

The current state-of-the-art treatment of SIBO is the provision of a short course (10-14 days) of antibiot-ics (Table 4). Thus far, rifaximin, a rifampin derivative, is the antibiotic that has been most widely recognized and published for its use in the treatment of SIBO.19 Additionally, SIBO has been implicated as a major con-tributing pathophysiological factor in IBS. Over the past decade, patients with IBS are increasingly turning to complementary and alternative medicine (CAM) options for symptoms relief and disease manage-ment.20 Herbal remedies and nutraceutical supple-ments continue to dominate as the most common forms of CAM used for IBS patients.21 A number of herbs have a long tradition of antimicrobial activity,22 thus we hypothesized that the use of plant extracts possessing antimicrobial activity would be as effective as antibiotic therapy for patients with an abnormal LBT and the diagnosis of SIBO.

METHODSStudy Participants

The medical records at a single tertiary-care refer-ral center from October 2006 to November 2010 were reviewed as part of an institutional IRB-approved proto-col. Study participants were included in the analysis if they had: (1) symptoms suggestive of SIBO, (2) an initial positive LBT, (3) completed a prescribed regimen of either rifaximin or herbal therapy, and (4) received a post-treatment LBT. Symptoms considered to be sug-gestive of SIBO included otherwise unexplained abdominal discomfort, cramping, bloating, flatulence, eructation, diarrhea, worsening of symptoms after meal ingestion, and low serum B12. Criteria considered to be risk factors for SIBO included prior history of gas-tric bypass surgery, known gastrointestinal motility disorder, collagen vascular disease, IBS (association), pancreatic insufficiency, and chronic proton-pump inhibitor (PPI) use. Exclusion criteria included those patients aged <18 or >85 years, use of antibiotics within 3 months, and failure to comply with regimen or to have a follow-up LBT. A subset of patients who (1) com-pleted the rifaximin regimen, (2) had persistently posi-tive post-treatment LBT, (3) subsequently completed a prescribed herbal or triple antibiotic regimen, and (4) had a post-herbal therapy LBT were defined as “rifaxi-min non-responders.”

Lactulose Breath Testing ProtocolStudy participants followed a standard prepara-

tion protocol prior to the procedure.23 No laxatives

were to be taken for at least a week prior to the test. One day prior, test subjects were advised to avoid high-fiber foods, butter, margarine, and sodas and asked to fast for 12 hours before the test, consuming no food except water. Subjects were advised not to smoke, sleep, or exercise vigorously up to 30 minutes before or at any time during the test.

Table 1ConditionsThatPredisposeTowardtheDevelopmentofSmallIntestineBacterialOvergrowth4-7

Achlorhydria(surgical,iatrogenic,autoimmune)

Motorabnormalities

Scleroderma

Intestinalpseudo-obstruction

Diabeticenteropathy

Vagotomy

Abnormalcommunicationbetweencolonandsmallbowel

Fistulasbetweencolonandsmallbowel

Resectionofileocecalvalve

Structuralabnormalities

Systemicandintestinalimmunedeficiencystates

Surgicalloops(BillrothII,entero-enteroanastomosis,Rou-en-Y)

Duodenalorjejunaldiverticula

Partialobstructionofsmallbowel(stricture,adhesions,tumors)

LargesmallIntestinediverticulosis

Systemicdiseases(celiacdisease,cirrhosis,pancreaticexocrineinsufficiency,non-alcoholicfattyliverdisease)

Alcoholism

Table 2 ProtectiveFactorsThatProtectAgainsttheDevelopmentofSmallIntestineBacterialOvergrowth4,8,9

•Gastricacid

•Pancreaticenzymes

•Bileacids

•Cholecystectomy

•Motility

•Migratingmotorcomplex

•Biofilm

•SecretoryimmunoglobulinA

Table 3ExtrinsicFactorsThatAltertheGutMicrobiomeandMayInfluencetheDevelopmentofSmallIntestineBacterialOvergrowth4

FODMAPsa(fructose,lactose,galactans,fructans,sugaralcohols)

Protonpumpinhibitors

Anti-motilityagents

Fiber

Prebiotics

Probiotics

Antibiotics

aFODMAPsisanacronymforagroupofhighlyfermentablefoods(FermentableOligo-,Di-,MonosaccharidesandPolyols).



Original Research

A QuinTron Gas Microanalyzer (QuinTron Instrument Company, Inc, Milwaukee, Wisconsin) was used to detect breath hydrogen in samples. Baseline breath hydrogen was obtained on all subjects prior to the ingestion of 10 gm of lactulose in 30 cc of water. Serial breath hydrogen analysis was obtained every 20 minutes after ingestion of lactulose up to a maximum of 3 hours. The test was considered positive if it showed one or more of the following24: (1) a baseline breath concentration of >10 parts per million (ppm) for hydro-gen or >7 ppm for methane only if patients were compli-ant with their preparation or (2) an increase within 90 minutes (small intestine) that was followed by a larger peak (colonic), indicative of a positive study (with a decrease of at least 5 ppm following the first peak). The

first increase had to have one of the following to be con-sidered positive: (1) an increase of at least 12 ppm meth-ane over the baseline by 90 minutes or (2) if producing hydrogen only, an increase of at least 20 ppm hydrogen over the baseline by 90 minutes. All breath tests were evaluated by a single experienced reader who was blinded to the treatment regimen (GM).

TreatmentSubjects with newly diagnosed SIBO by LBT were

given two open-label treatment choices based upon individualized treatment preference; either two 200 mg rifaximin tablets three times daily (TID) or 2 capsules twice daily of the following commercial herbal prepara-tions; Dysbiocide and FC Cidal (Biotics Research Laboratories, Rosenberg, Texas) or Candibactin-AR and Candibactin-BR (Metagenics, Inc, Aliso Viejo, California) for 4 consecutive weeks immediately followed by a repeat LBT. Table 5 illustrates the details regarding the composition for each herbal preparation. The cost of herbal therapy was no more than $120 for a 30-day sup-ply. The primary outcome was the proportion of patients in each group who had a negative post-treat-ment LBT. Rifaximin non-responders were then pre-scribed either the herbal protocol or triple antibiotics (clindamycin 300 mg TID, metronidazole 250 mg TID, neomycin 500 mg TID) for 4 additional weeks. The sta-tistical methods applied to analyze the results were the student t-test and chi-squared test. The study was approved by the Johns Hopkins University (Baltimore, Maryland) Internal Review Board.

RESULTSA flow chart of the study design and results are

shown in the Figure. Three hundred ninety-seven

Table 4AntibioticRegimensUsedforSmallIntestineBacterialOvergrowth18

Agent Dose Frequency

Amoxicillin-clavulanate 500mgPO 3times/day

Cephalexin 250mgPO 4times/day

Chloramphenicol 250mgPO 4times/day

Ciprofloxacin 500mgPO twicedaily

Doxycycline 100mgPO twicedaily

Metronidazole 250mgPO 3times/day

Neomycin 500mgPO twicedaily

Norfloxacin 400mgPO twicedaily

Rifaximin 400mgPO 3times/day

Tetracycline 250mgPO 4times/day

Trimethoprim-sulfamethoxazole

1double-strengthtabletPO

twicedaily

Abbreviation:PO,peros(bymouth).

Table 5 HerbalPreparationsfortheTreatmentofSmallIntestineBacterialOvergrowth

FC Cidal Dysbiocide Candibactin-AR Candibactin-BR

Proprietaryblend-500mg:1capsule

ProprietaryBlend950mgper2capsules

OneCapsulecontains: TwoCapsulescontain:

Tinosporacordifolia(stem) Dillseed RedThymeoil(thymusvulgaris,providing30%-50%thymol)0.2mL

Coptisrootandrhizomeextract(coptischinensis,containingberberine)30mg

Equisetumarvense(stem) StemonaSessilifoliapowderandextract

OreganoOil(origanumvulgare,pro-viding55%to75%carvacrol)0.1mL

IndianBarberryrootextract(berberisaristata,containingberberine)70mg

PauD’Arco(innerbark) ArtemisiaAbsinthiumshootsandleavesextract,

Sageleaf5.5:1extract(salviaofficinalis)75mg

BerberineSulfate400mg•Proprietary4:1Extract300mg:Coptisrootandrhizome(coptischinensis)

Thymusvulgaris(aerialpart) PulsatillaChinensisrhizomepowderandextract

LemonBalmleaf5:1extract(melissaofficinalis)50mg

ChineseSkullcaproot(scutellariabaicalensis)

Artemisiadracunculus(leaf) BruceaJavanicapowderandextract

Philodendronbark(phellodendronchinense)

Sidacordifolia(aerialpart) PicrasmaExcelsabarkextract Gingerrhizome(zingiberofficinale)

Oleaeuropaea(leaf) AcaciaCatechustemextract ChineseLicoriceroot(glycyrrhizauralensis)

HedyotisDiffusapowderandextract

ChineseRhubarbrootandrhizome(rheumofficinale)

Yarrowleafandflowerextract(achilleamillefolium).

ChineseRhubarbrootandrhizome(rheumofficinale).



patients were offered LBT for suspected SIBO, of which 252 (63.5%) were positive; 87 of these patients did not pursue treatment, and 61 of those who underwent therapy did not undergo repeat LBT. The remaining 104 patients were provided the option of two treat-ment arms as per the patients’ choice and underwent post-treatment LBT. Rifaximin was completed by 67 patients, and 37 completed herbal therapy. Results were tabulated only for those who completed therapy. There was no difference in the mean age of patients who chose rifaximin (47.55 ± 15.73) and those on

herbal therapy (41.6 ± 16.3) (P=.30). There was a gen-der skewing of participants as 48/67 (71%) of the rifaximin arm and 29/37 (78%) of the herbal arm were females (Table 6). Of the 67 patients who completed the rifaximin arm, 9 (13%) had risk factors for SIBO (diabetes mellitus, gastroparesis, narcotics, connective tissue disease, etc) while 7 (19%) in the herbal arm had risk factors (P=.46). Of the 252 individuals who tested positive for SIBO by LBT, 160 (63.5%) had IBS as diag-nosed by the Rome III criteria. Of the 37 patients who received herbs, 17 (46%) had a negative follow-up LBT

397Received LBT

Positive LBT252

Positive LBT20

Positive LBT6

Positive LBT44

Negative LBT145

104Met inclusion criteria

87 lacked treatmentdocumentation

+61 no repeat LBT

Rifaximin67

Herbal therapy37

No therapy rescue14

No herbal rescue30

Negative LBT23

Negative LBT17

Negative LBT8

FigureFlowchartofthestudydesign:397patientswererecruitedtoparticipateinthestudyandunderwentlactulosebreathhydrogentesting(LBT),252werefoundtobeLBTpositivewhile145werenegative.Duetolackofprotocoladherence,only104ofthosewhowerehadpositiveLBTmetourinclusioncriteriaforthestudy,with67optingforRifaximintherapyand37preferringherbals.Forty-fourofthe67(65.7%)subjectstreatedwithRifaximinfailedtorespondandhadpositiveLBTaftertherapywithonly34.3%responding.Herbaltherapieswereassociatedwitha(17/37)45.9%responseratewith(20/37)54.1%havingpost-treatmentpositiveLBT.ForthosewhofailedthefirstroundofRifaximintherapy,acrossovertrialshoweda8/14(57.1%)responserateforherbalsinthosewhofailedRifaximin.



Original Research

compared to 23/67 (34%) of rifaximin users (P=.24) (Table 7). The odds ratio of having a negative LBT if on herbal therapy as compared to rifaximin was 1.85 (CI=0.77-4.41, P=.17) once adjusted for age, gender, SIBO risk factors, and IBS status (Table 8). Fourteen of the 41 (34.1%) rifaximin non-responders were offered herbal rescue therapy; 8 of the 14 (57.1%) had a nega-tive LBT after completing the rescue herbal therapy. Ten of the 41 (24.4%) rifaximin non-responders were offered rescue therapy with triple antibiotics, and 6 of the 10 (60%) had a negative LBT after completing the rescue herbal therapy. Rescue therapy with herbals in rifaximin non-responders was not different (P=1.0). The average age of those SIBO patients who cleared the LBT post-rescue herbal therapy was 37.4 ± 17 years, which was not different than non-responders (41.5 ± 11.6, P=.62) (Table 9). The prevalence of IBS subtype, known risk factor(s) for SIBO, or gender status did not predict response to herbal rescue therapy (Table 9). Adverse effects (AE) were reported among the rifaxi-

min treated arm (6/67; 9.0%) including 1 case of ana-phylaxis, 2 cases of hives, 2 cases of diarrhea, and 1 case of Clostridium difficile (post-treatment). One case of diar-rhea (non–Clostridium difficile) was reported in the herbal therapy arm (1/37; 2.7%) (P=.22)

DISCUSSIONThere is an ongoing resurgence of interest in the

role of gut microbiota-host interactions in both health

Table 6 DemographicInformationofRifaximinvsHerbalUsers

Rifaximin (n=67) Herbal (n=37) P value

Age(yrs) 47.55±15.73 41.6±16.3 .07

Percentfemale 48(71%) 29(78%) .45

RiskFactorsforSIBO 9(13%) 7(19%) .46

Diabetesmellitus 4(6%) 0(0%) .12

Gastroparesis 2(3%) 1(3%) .93

Narcotic 1(1%) 3(8%) .09

CTD 2(3%) 4(11%) .1

Anyriskfactor 9(13%) 7(19%) .46

IBS 53(79%) 25(68%) .19

Distribution of IBS by Subtypes .08

None 14(21%) 12(32%)

Diarrheapredominant 22(32%) 6(16%)

Constipationpredominant 16(24%) 12(32%)

Mixed 14(21%) 4(11%)

UnclassifiedIBS 1(1%) 3(8%)

NegativeLBTafterRx 23(34%) 17(46%) .24

Table 7 ResultsofIBSSubjectsUndergoingInterventionforPositiveLactuloseBreath

HydrogenTestingforSmallIntestineBacterialOvergrowth(n=104)

Characteristics Rifaximin Herbs P value

Number 67 37 N/A

Age (y), SD, range 44.4± 14.8(19-81) 41.3±14.8(19-76) .33

Gender Female, n (%)Male, n (%)

48(71)19(29)

29(78)8(22)

.97

Responses (n) 26 15 N/A

Response Rate (%) 34 46 .24

Adverse Events (n, %) 2,2.9 1,2.7 .83

Table 8 OddsRatios(OR)forNegativeLBTComparingHerbalTherapytoRifaximin

OR Confidence Interval P value

Unadjusted 1.63 0.72-3.70 .24

AdjustedforAgeandGender

1.62 0.70-3.77 .16

FullyAdjusted* 1.85 0.77-4.41 .17

*Adjustedforage,gender,smallintestinebacterialovergrowthriskfactors,andirritablebowelsyndromestatus.



and disease.25 The gut microbiota is a finely balanced ecosystem that helps regulate key vital functions for the host, including immunity, barrier defense, biotrans-formation of toxins and carcinogens, and much more.26 As discussed in more detail by Okeke et al in this issue of Global Advances in Health and Medicine, imbalances in the gut microbiome (also known as dysbiosis) have been linked to the development of disorders of mood and behavior, Alzheimer’s disease, and numerous gas-trointestinal and systemic disorders including inflam-matory bowel disease, diabetes, obesity, and cardiovas-cular disease.27,28 Bacterial dysbiosis in SIBO can dis-rupt epithelial tight junctions increasing small intes-tine paracellular permeability, translocation of endo-toxin, and induction of proinflammatory cytokines.29-31 SIBO can have a number of extraintestinal manifesta-tions such as rosacea, restless legs syndrome,17,32 arthralgias, anemia, interstitial cystitis,33 chronic pros-tatitis,34 and polyneuropathy.1 A large body of work has linked bacterial dysbiosis of the small bowel and endotoxemia to non-alcoholic steatohepatitis and pro-gression of alcoholic liver disease, non-alcoholic fatty liver disease, obesity, and others.35-38 SIBO is a widely prevalent condition in the practice of gastroenterology that is chronic and recurrent for patients and lacks clear treatment guidelines for practitioners. Given the role of the gut microbiome in health and dysbiosis in disease, SIBO is an important entity in clinical practice to recognize and treat.

Rifaximin is the most commonly studied antibiot-ic treatment for SIBO, with an overall breath test resolu-tion rate of 49.5% (95% confidence interval, CI 44.0-55.1) in 8 clinical trials.18 A recent meta-analysis report-ed that the therapeutic efficacy of rifaximin to treat SIBO in the setting of IBS showed benefit; however, the therapeutic gain was only 9.8%, and the number need-ed to treat is 10.2 with mild heterogeneity (P=.25, I(2)=26%).39 Additionally, rifaximin is currently not approved by the US Food and Drug Administration (FDA) for the treatment of SIBO and is only labeled for hepatic encephalopathy. Furthermore, a month’s sup-ply of rifaximin retails for $1247.39, and according to Medicare part D, a patient’s copay in 2014 will be $638.09 for preferred ($703.70, non-preferred) pharma-

cy or mail-in.40 Antibiotics may also produce a wide range of toxicity (Clostridium difficle colitis, antibiotic induced diarrhea, anaphylaxis, Steven’s Johnson reac-tions, hemolytic-uremic syndrome, etc).41 Antibiotics have also been postulated to have pervasive adverse effects on the gut microbiome and protective biofilm layer.42 In fact, a 7-day course of clindamycin has been shown to reduce commensal flora and gut microbial diversity and select antibiotic-resistant genes for over 2 years.43 Thus, research into more effective and safer therapeutic options for SIBO are ongoing.

The present study demonstrates that herbal thera-py may be as effective as antibiotic therapy in the treat-ment of SIBO, as indirectly measured by normalization of the lactulose breath test abnormalities. Complementary and alternative medicine has gained wide popularity among the United States population, with up to 50% of patients using at least one form of alternative therapy.44 In addition, it has been noted that the majority of alternative medicine users are patients with chronic conditions. Examples include relaxation techniques and acupuncture for migraines, chiroprac-tic for back problems, and herbal therapy and relax-ation for digestive problems.44 Drossman et al reported based on an international survey that approximately 37% of patients with functional digestive disorders seek complementary and alternative therapies to con-trol their symptoms.45 More recent data indicates that up to 51% of patients with IBS report using CAM.20,21 Since CAM has gained popularity among patients with gastrointestinal diseases, especially functional disor-ders, physicians should familiarize themselves with available CAM therapies.46 Alternative therapies com-monly used by IBS patients that have some level of sci-entific basis in the literature include acupuncture, fiber, peppermint oil, herbal, traditional, yoga, massage, meditation, mind, relaxation, probiotics, hypnothera-py, psychotherapy, cognitive therapy, and behavioral therapies.47 The use of antimicrobial herbs to treat SIBO has not been previously reported in the literature. A number of herbs exist that have known antimicrobi-al activity.48-53 In the current study, we chose a combi-nation of herbal preparations to provide broad-spec-trum coverage against enteric coliforms.54,55 Oil of

Table 9 DemographicInformationofRifaximinNonrespondersAfterHerbalRescueTherapy

Responder (n=8) Nonresponder (n=6) P value

Age+/-SD 37.4+/-17 41.5+/-11.57 0.62

Female(%) 5(62.5%) 4(67%) 0.87

IBSsubtype 0.74

None 1(12.5%) 1(16.7%)

Diarrheapredominant 1(14%) 2(40%)

Constipationpredominant 3(43%) 1(20%)

Mixed 3(60%) 2(40%)

AnyRiskFactorforSIBOa 2(25%) 1(17%) 0.71

aDefinedasnarcoticuse,gastroparesis,diabetesmellitus,andconnectivetissuedisease.



Original Research

oregano (Origanum vulgare) is a well-documented botanical that directly kills or strongly inhibits the growth of intestinal microbes.56,57 Oil of oregano has other beneficial properties such as inducing apoptosis in human colon cancer caco2 cells.58 Berberine extracts and thymus vulgaris are also well known for their broad antibacterial activities.56,59-61 Wormwood (Artemisia absinthium) has substantial antimicrobial and anti-inflammatory properties that may be impor-tant to the pathogenesis of SIBO and has been used to successfully induce remission of Crohn’s Disease.37,62 There are other herbals used in our study that have noteworthy properties. Lemon balm offers anti-anxi-ety and antidepressant effects that may benefit patients with IBS, while coptis root has growth-inhibitory effects on human bacteria.63-65 Red thyme essential oil inhibits the growth of Escherichia coli O157: H7 and Staphylococcus aureus.66 Indian Barbarry root extract (Berberis aristata) contains berberine and has antimi-crobial, anti-inflammatory, and antidiarrheal proper-ties.67 Equisetum arvense L. was shown to possesses a broad spectrum of a very strong antimicrobial activity against a variety of enteric microorganisms including Staphylococcus aureus (S aureus), Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella enteritidis and the fungi Aspergillus niger and Candida albicans.68 Thymus vulgaris has potent antimi-crobial and anti-inflammatory actions.69-72 Olea europaea inhibits the growth of a number of staphylococcal species including S aureus.73

Rifaximin is a non-absorbable oral antibiotic, first introduced in Italy in 1987 and in the United States in 2004, that has been approved for a variety of indica-tions and is presently an antibiotic of choice for SIBO.74 Rifaximin is presently the best studied antibiotic with an overall breath test resolution rate of 49.5% (95% confidence interval, CI 44.0-55.1).18 Lauritano et al in 2009 showed that rifaximin is superior to metronida-zole in the treatment of SIBO; however, recurrence rates after treatment with antibiotics is high as evi-denced by high breath test positivity.75 In our study, we demonstrated that 46% of patients normalized their LBT with herbal therapy. There was no statistical difference between antimicrobial herbs (46%) and rifaximin (34%) (P=.24). Patients were offered the choice of either therapy. SIBO tends to be a recurrent disease, and frequent antibiotic use may have long-term adverse effects on the gut microbiome and be costly; thus, herbal therapy may be a reasonable treat-ment option for patients with SIBO. In our study, the side effect profile of herbs when compared to rifaximin was not statistically different with a P=.22. However, the prevalence of side effects in the Rifaximin group was 9% (6/67) including C difficle and 2 non-C difficle–associated diarrhea. In the herbal group, only 1 case of non-C difficle–associated diarrhea (1%) was observed. These observations are contrary to popular beliefs. Perhaps the herbal therapies are less disruptive to the gut microbiome and while producing efficacy in

resolving SIBO there appears to be less risk of C difficle; extended trials will need to confirm this hypothesis. The fear of bacterial resistance including opportunis-tic infections such as Clostridium difficile raises con-cerns among recurrent antibiotic users. The rifaximin non-responders who received herbal therapy were equally successful in resolving SIBO via the LBT as were triple antibiotics, which had much higher cost and risk of toxicity. Thus, herbal therapy appears to be effective in the treatment of SIBO patients that is ini-tially refractory to rifaximin. Patients who were treat-ed with herbs were not different than those who received rifaximin with respect to the number of pre-disposing factors for SIBO, and thus the equivalence in response was not due to disparities in underlying con-ditions. Induction of achlorhydria by acid-suppressive medications (eg, PPIs) has been studied as a potential risk factor for SIBO, with a recent meta-analysis of 11 studies revealing that a pooled OR of SIBO in PPI users vs nonusers was 2.282 (95% confidence interval [CI], 1.238-4.205) when duodenal/jejunal aspirate culture was used to diagnose SIBO but not for glucose hydro-gen breath testing.76 In contrast, in our study, concur-rent PPI use did not appear to influence response to either herbal therapies (P=.27) or rifaximin (P=.10).

Limitations of this study include the fact that it was a retrospective chart review and not a prospective, randomized controlled trial. Furthermore, there was heterogeneity and multiplicity of herbs used and, addi-tionally, diet was not controlled. Our patients were also not formally assessed for symptom resolution using a standardized questionnaire. The cost of the herbal regi-men is traditionally not covered by commercial insur-ance; however, the cost of the herbals is relatively low and many individuals did find coverage through their flexible spending accounts.

In summary, we conclude that in the setting of SIBO, patients can be given the choice of antibiotic or herbal therapy depending on their individual prefer-ence with similar response rates and safety profiles. In addition, patients who are refractory to rifaximin can receive herbal therapy as a potential rescue therapy with equivalent results to triple antibiotics. This deci-sion is left at the discretion of the treating physician and the patient depending on the clinical setting and the patient’s inclination. Future prospective studies that consolidate the antimicrobial herbal regimen to a single agent would potentially enable randomization and blinding, improve patient compliance, and dimin-ish associated costs in this challenging gastrointesti-nal disorder.

REFERENCES1. Bures J, Cyrany J, Kohoutova D, et al. Small intestinal bacterial over-

growth syndrome. World J Gastroenterol. 2010;16(24):2978-90.2. Ford AC, Spiegel BM, Talley NJ, Moayyedi P. Small intestinal bacterial

overgrowth in irritable bowel syndrome: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2009;7(12):1279-86.

3. Choung RS, Ruff KC, Malhotra A, et al. Clinical predictors of small intes-tinal bacterial overgrowth by duodenal aspirate culture. Aliment Pharmacol Ther. 2011;33(9):1059-67.

4. Bohm M, Siwiec RM, Wo JM. Diagnosis and management of small intesti-



nal bacterial overgrowth. Nutr Clin Pract. 2013;28(3):289-99.5. Batt RM. Exocrine pancreatic insufficiency. Vet Clin North Am Small

Anim Pract. 1993;23(3):595-608.6. Jacobs C, Coss Adame E, Attaluri A, Valestin J, Rao SS. Dysmotility and

proton pump inhibitor use are independent risk factors for small intesti-nal bacterial and/or fungal overgrowth. Aliment Pharmacol Ther. 2013;37(11):1103-11.

7. Tursi A, Brandimarte G, Giorgetti G. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointesti-nal symptoms after gluten withdrawal. Am J Gastroenterol. 2003;98(4):839-43.

8. Gabbard SL, Lacy BE, Levine GM, Crowell MD. The Impact of alcohol consumption and cholecystectomy on small intestinal bacterial over-growth. Dig Dis Sci. 2013.

9. Macfarlane S. Microbial biofilm communities in the gastrointestinal tract. J Clin Gastroenterol. 2008;42 Suppl 3 Pt 1:S142-3.

10. Scarpellini E, Gabrielli M, Lauritano CE, et al. High dosage rifaximin for the treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2007;25(7):781-6.

11. Park JS, Yu JH, Lim HC, et al. [Usefulness of lactulose breath test for the prediction of small intestinal bacterial overgrowth in irritable bowel syndrome]. Korean J Gastroenterol. 2010;56(4):242-8.

12. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98(2):412-9.

13. Corazza GR, Menozzi MG, Strocchi A, et al. The diagnosis of small bowel bacterial overgrowth. Reliability of jejunal culture and inadequacy of breath hydrogen testing. Gastroenterology. 1990;98(2):302-9.

14. Pimentel M, Wallace D, Hallegua D, et al. A link between irritable bowel syndrome and fibromyalgia may be related to findings on lactulose breath testing. Ann Rheum Dis. 2004;63(4):450-2.

15. Parodi A, Paolino S, Greco A, et al. Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol. 2008;6(7):759-64.

16. Shanab AA, Scully P, Crosbie O, et al. Small intestinal bacterial over-growth in nonalcoholic steatohepatitis: association with toll-like recep-tor 4 expression and plasma levels of interleukin 8. Dig Dis Sci. 2011;56(5):1524-34.

17. Weinstock LB, Fern SE, Duntley SP. Restless legs syndrome in patients with irritable bowel syndrome: response to small intestinal bacterial overgrowth therapy. Dig Dis Sci. 2008;53(5):1252-6.

18. Shah SC, Day LW, Somsouk M, Sewell JL. Meta-analysis: antibiotic thera-py for small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2013;38(8):925-34.

19. Saadi M, McCallum RW. Rifaximin in irritable bowel syndrome: ratio-nale, evidence and clinical use. Ther Adv Chronic Dis. 2013;4(2):71-5.

20. Kong SC, Hurlstone DP, Pocock CY, Walkington LA, Farquharson NR, Bramble MG, et al. The Incidence of self-prescribed oral complementary and alternative medicine use by patients with gastrointestinal diseases. J Clin Gastroenterol. 2005;39(2):138-41.

21. Haas L, McClain C, Varilek G. Complementary and alternative medicine and gastrointestinal diseases. Curr Opin Gastroenterol. 2000;16(2):188-96.

22. Lai PK, Roy J. Antimicrobial and chemopreventive properties of herbs and spices. Curr Med Chem. 2004;11(11):1451-60.

23. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95(12):3503-6.

24. Lupascu A, Gabrielli M, Lauritano EC, et al. Hydrogen glucose breath test to detect small intestinal bacterial overgrowth: a prevalence case-control study in irritable bowel syndrome. Aliment Pharmacol Ther. 2005;22(11-12):1157-60.

25. Aitken JD, Gewirtz AT. Gut microbiota in 2012: Toward understanding and manipulating the gut microbiota. Nat Rev Gastroenterol Hepatol. 2013;10(2):72-4.

26. Guinane CM, Cotter PD. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Therap Adv Gastroenterol. 2013;6(4):295-308.

27. Azad MB, Konya T, Maughan H, et al. Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ. 2013.

28. Major G, Spiller R. Irritable bowel syndrome, inflammatory bowel dis-ease and the microbiome. Curr Opin Endocrinol Diabetes Obes. 2014;21(1):15-21.

29. Lauritano EC, Valenza V, Sparano L, et al. Small intestinal bacterial over-growth and intestinal permeability. Scand J Gastroenterol . 2010;45(9):1131-2.

30. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intesti-nal permeability, endotoxaemia, and tumour necrosis factor alpha in the

pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48(2):206-11.31. Riordan SM, McIver CJ, Thomas DH, Duncombe VM, Bolin TD, Thomas

MC. Luminal bacteria and small-intestinal permeability. Scand J Gastroenterol. 1997;32(6):556-63.

32. Weinstock LB, Walters AS. Restless legs syndrome is associated with irri-table bowel syndrome and small intestinal bacterial overgrowth. Sleep Med. 2011;12(6):610-3.

33. Weinstock LB, Klutke CG, Lin HC. Small intestinal bacterial overgrowth in patients with interstitial cystitis and gastrointestinal symptoms. Dig Dis Sci. 2008;53(5):1246-51.

34. Weinstock LB, Geng B, Brandes SB. Chronic prostatitis and small intestinal bacterial overgrowth: effect of rifaximin. Can J Urol. 2011;18(4):5826-30.

35. Imajo K, Yoneda M, Ogawa Y, Wada K, Nakajima A. Microbiota and non-alcoholic steatohepatitis. Semin Immunopathol. 2013.

36. Yan AW, Fouts DE, Brandl J, et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology. 2011;53(1):96-105.

37. Imajo K, Yoneda M, Ogawa Y, Wada K, Nakajima A. Microbiota and non-alcoholic steatohepatitis. Semin Immunopathol. 2014;36(1):115-32.

38. Jouet P, Coffin B, Sabate JM. Small intestinal bacterial overgrowth in patients with morbid obesity. Dig Dis Sci. 2011;56(2):615; author reply -6.

39. Menees SB, Maneerattannaporn M, Kim HM, Chey WD. The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol. 2012;107(1):28-35; quiz 6.

40. Tillisch K. Complementary and alternative medicine for functional gas-trointestinal disorders. Gut. 2006;55(5):593-6.

41. Zhang Y, Dong J, Qiao Y, He J, Wang T, Ma S. Efficacy and safety profile of antibiotic prophylaxis usage in clean and clean-contaminated plastic and reconstructive surgery: a meta-analysis of randomized controlled trials. Ann Plast Surg. 2014;72(1):121-30.

42. Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6(11):e280.

43. Jernberg C, Lofmark S, Edlund C, Jansson JK. Long-term impacts of anti-biotic exposure on the human intestinal microbiota. Microbiology. 2010;156(Pt 11):3216-23.

44. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national sur-vey. JAMA. 1998;280(18):1569-75.

45. Drossman DA, Morris CB, Schneck S, et al. International survey of patients with IBS: symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit. J Clin Gastroenterol. 2009;43(6):541-50.

46. Mullin GE, Pickett-Blakely O, Clarke JO. Integrative medicine in gastroin-testinal disease: evaluating the evidence. Expert Rev Gastroenterol Hepatol. 2008;2(2):261-80.

47. Magge SS, Wolf JL. Complementary and alternative medicine and mind-body therapies for treatment of irritable bowel syndrome in women. Womens Health (Lond Engl). 2013;9(6):557-67.

48. Lee MH, Kwon HA, Kwon DY, Park H, Sohn DH, Kim YC, et al. Antibacterial activity of medicinal herb extracts against Salmonella. Int J Food Microbiol. 2006;111(3):270-5.

49. Zhu CL, Li MY. [Inhibition of extracts from 17 Chinese herbs on peri-odontal pathogenic microbes] . Shanghai Kou Qiang Yi Xue. 2006;15(4):434-6.

50. Nielsen PV, Rios R. Inhibition of fungal growth on bread by volatile com-ponents from spices and herbs, and the possible application in active packaging, with special emphasis on mustard essential oil. Int J Food Microbiol. 2000;60(2-3):219-29.

51. Eftekhar F, Nariman F, Yousefzadi M, Hadiand J, Ebrahimi SN. Anti-Helicobacter pylori activity and essential oil composition of Thymus car-amanicus from Iran. Nat Prod Commun. 2009;4(8):1139-42.

52. Gutierrez J, Barry-Ryan C, Bourke P. Antimicrobial activity of plant essen-tial oils using food model media: efficacy, synergistic potential and inter-actions with food components. Food Microbiol. 2009;26(2):142-50.

53. Talei GR, Meshkatalsadat MH. Antibacterial activity and chemical consti-tutions of essential oils of Thymus persicus and Thymus eriocalyx from west of Iran. Pak J Biol Sci. 2007;10(21):3923-6.

54. Kalemba D, Kunicka A. Antibacterial and antifungal properties of essen-tial oils. Curr Med Chem. 2003;10(10):813-29.

55. Schillaci D, Napoli EM, Cusimano MG, Vitale M, Ruberto A. Origanum vulgare subsp. hirtum essential oil prevented biofilm formation and showed antibacterial activity against planktonic and sessile bacterial cells. J Food Prot. 2013;76(10):1747-52.

56. Arcila-Lozano CC, Loarca-Pina G, Lecona-Uribe S, Gonzalez de Mejia E. [Oregano: properties, composition and biological activity]. Arch Latinoam Nutr. 2004;54(1):100-11.

57. Saeed S, Tariq P. Antibacterial activity of oregano (Origanum vulgare Linn.) against gram positive bacteria. Pak J Pharm Sci. 2009;22(4):421-4.

58. Savini I, Arnone R, Catani MV, Avigliano L. Origanum vulgare induces apoptosis in human colon cancer caco2 cells . Nutr Cancer.



Original Research

2009;61(3):381-9.59. Han J, Lin H, Huang W. Modulating gut microbiota as an anti-diabetic

mechanism of berberine. Med Sci Monit. 2011;17(7):RA164-7.60. Yang Y, Ye XL, Li XG, Zhen J, Zhang B, Yuan L. Synthesis and antimicrobial

activity of 8-alkylberberine derivatives with a long aliphatic chain. Planta Med. 2007;73(6):602-4.

61. Baser KH. Biological and pharmacological activities of carvacrol and car-vacrol bearing essential oils. Curr Pharm Des. 2008;14(29):3106-19.

62. Juteau F, Jerkovic I, Masotti V, et al. Composition and antimicrobial activ-ity of the essential oil of Artemisia absinthium from Croatia and France. Planta Med. 2003;69(2):158-61.

63. Raines T, Jones P, Moe N, Duncan R, McCall S, Ceremuga TE. Investigation of the anxiolytic effects of luteolin, a lemon balm flavo-noid in the male Sprague-Dawley rat. AANA J. 2009;77(1):33-6.

64. Taiwo AE, Leite FB, Lucena GM, et al. Anxiolytic and antidepressant-like effects of Melissa officinalis (lemon balm) extract in rats: Influence of administration and gender. Indian J Pharmacol. 2012;44(2):189-92.

65. Chae SH, Jeong IH, Choi DH, Oh JW, Ahn YJ. Growth-inhibiting effects of Coptis japonica root-derived isoquinoline alkaloids on human intestinal bacteria. J Agric Food Chem. 1999;47(3):934-8.

66. Zarringhalam M, Zaringhalam J, Shadnoush M, Safaeyan F, Tekieh E. Inhibitory Effect of Black and Red Pepper and Thyme Extracts and Essential Oils on Enterohemorrhagic Escherichia coli and DNase Activity of Staphylococcus aureus. Iran J Pharm Res. 2013;12(3):363-9.

67. Joshi PV, Shirkhedkar AA, Prakash K, Maheshwari VL. Antidiarrheal activity, chemical and toxicity profile of Berberis aristata. Pharm Biol. 2011;49(1):94-100.

68. Radulovic N, Stojanovic G, Palic R. Composition and antimicrobial activi-ty of Equisetum arvense L. essential oil. Phytother Res. 2006;20(1):85-8.

69. Fachini-Queiroz FC, Kummer R, Estevao-Silva CF, Carvalho MD, Cunha JM, Grespan R, et al. Effects of Thymol and Carvacrol, Constituents of Thymus vulgaris L. Essential Oil, on the Inflammatory Response. Evid Based Complement Alternat Med. 2012;2012:657026.

70. Gancevici GG, Popescu C. Natural inhibitors of complement. III. Inactivation of the complement cascade in vitro by vegetal spices (Ocimum basilicum, Artemisia dracunculus and Thymus vulgaris). Arch Roum Pathol Exp Microbiol. 1987;46(4):321-31.

71. Hammad M, Sallal AK, Darmani H. Inhibition of Streptococcus mutans adhesion to buccal epithelial cells by an aqueous extract of Thymus vul-garis. Int J Dent Hyg. 2007;5(4):232-5.

72. Esmaeili D, Mobarez AM, Tohidpour A. Anti-helicobacter pylori activi-ties of shoya powder and essential oils of thymus vulgaris and eucalyp-tus globulus. Open Microbiol J. 2012;6:65-9.

73. Ali NH, Faizi S, Kazmi SU. Antibacterial activity in spices and local medicinal plants against clinical isolates of Karachi, Pakistan. Pharm Biol. 2011;49(8):833-9.

74. Pimentel M. Review of rifaximin as treatment for SIBO and IBS. Expert Opin Investig Drugs. 2009;18(3):349-58.

75. Lauritano EC, Gabrielli M, Scarpellini E, Lupascu A, Novi M, Sottili S, et al. Small intestinal bacterial overgrowth recurrence after antibiotic ther-apy. Am J Gastroenterol. 2008;103(8):2031-5.

76. Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol. 2013;11(5):483-90.

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